Malignant brain tumor accounts for about 2% of malignant neoplasm cases. In spite of the low occurrence rate of malignant brain tumor, it is difficult to prevent because there is no specific carcinogenic factor for this disease. Brain tumors comprise primary brain tumors growing from the brain or other related cell and metastatic brain tumors from cancerous cells of other parts of the body. The outbreak of brain cancer is generally slow and takes a few weeks to several years. Symptoms of brain cancer include nausea, headache or dysfunction of consciousness caused by the increase of brain pressure, seizure, hormonal abnormalities, and partial cerebral dysfunction, such as reduced sensing capabilities, aphasia, flaccid limbs, paresthesia, vision and visual field loss, etc.
Because malignant brain tumor cells spread and grow within normal tissues and are not easy to eradicate with surgery, therapy for brain cancer must be assisted with chemotherapy. However, most anti-cancer drugs cannot be transmitted to brain tumor cells for cytotoxic effects due to the obstruction of the special “blood brain barrier” within the brain, and thus, the therapy effect is limited. As a result, the average lifespan of patients with terminal brain cancer is usually no more than about a year.
Currently, temozolomide (TMZ) is one of the drugs commonly used to treat malignant brain tumor in clinic. It is an imidazole-tetrazine type oral chemotherapeutic drug and can pass through the blood brain barrier to kill brain tumor cells. Therefore, it can effectively inhibit tumor proliferation and further treat brain cancer. Temozolomide is particularly effective in gliomas (including glioblastoma multiforme tumor and anaplastic astrocytoma). However, the toxicity of temozolomide is high and produces side effects such as nausea, vomiting, headache, lack of strength, fatigue, anorexia, etc. Furthermore, temozolomide is generally combined with radiation therapy to enhance the therapeutic effects, resulting in more serious side effects.
Temozolomide is a methylating agent. It is generally believed that by methylating the oxygen at the 6th position in the guanine of DNA, temozolomide may distort the double-stranded DNA structure to inhibit DNA replication and lead to the death of cancer cells. However, such a mechanism will be inhibited by O6-methylguanine DNA-methyltransferase (MGMT) in cancer cells, because MGMT will remove abnormal methylation within the cell to perform repairing functions, thus, weakening the efficacy of temozolomide. As a result, tumor cells will produce resistance to temozolomide accordingly. The aforesaid inhibition effect of MGMT makes it necessary to increase the dosage of temozolomide in order to achieve the effectiveness. This will inevitably lead to more serious side effects and increase the burden on patients.
If the temozolomide-resistance of the tumor cells can be reduced effectively, it will be possible to avoid an unnecessary increase of temozolomide dosage and reduce the burden on patients. The study has revealed that the efficacy of temozolomide is not necessarily improved when the expression of MGMT within the brain cancer patient's body is inhibited (See Ranson et. al., Randomized Trial of the Combination of Lomeguatrib and Temozolomide Compared With Temozolomide Alone in Chemotherapy Naïve Patients With Metastatic Cutaneous Melanoma, J Clin Oncol, 2007. Vol. 25:2540-5, which is incorporated hereinto by reference).
Therefore, a method for effectively reducing the resistance of brain cancer cells to temozolomide is still needed to avoid unnecessary temozolomide overdose during therapy and reduce the burden on patients. In addition, if the efficacy of temozolomide can be improved while the temozolomide-resistance of brain cancer cells is reduced, it can provide further assistance to patients during the treatment and reduce their burden.